An Advance in Making Inclusion Complexes: US 2,620,716

 

This patent pertains to a treatment of crude petroleum which separates some fractions containing particular classes of chemical structures from other fractions containing other classes. It makes reference to making inclusion complexes that trap and make insoluble and hence filterable certain kinds of chemical structures while leaving undisturbed in the bulk oil other structural types.  Its examples use the chemical agents urea and thiourea but their use is not new and not the claimed invention. KiloMentor has written blogs about such inclusion complexes. They are in fact old.

What this inventor claims is new is the claimed discovery that certain ‘contacting agents’ accelerate and make more dependable the formation of these valuable complexes and by so doing makes their application practical.

So much for the generalities!! That is how patent lawyers talk!

The teaching that excites me is that straight chain hydrocarbon-like molecules quickly and dependably form insoluble, retrievable, filterable complexes with urea when stirred in neat acetic anhydride, neat sulfur dioxide, and ‘perhaps’ in neat furfural. 

Well, KiloMentor is interested in techniques that are promising for separating very similar chemical structures by rugged cheap methods that work at scale. Well, urea, sulfur dioxide, furfural, and acetic anhydride are inexpensive and urea inclusion complexes have the ability to separate straight chains from branched chains.

Phenylboronic Acid: A Functional Tag to Enable Simple Removal of Excess Reagent or Coproduct using Chromotropic Acid

Chromotropic Acid for Extracting Boronates

The KiloMentor Blog articles emphasize ways to make the workup, separation, and purification of the product from organic reactions more cost-effective. Often this is enabled by phase switching methods that quickly take the desired material into one bulk phase and byproducts, coproduces, and the processing chemicals into another.

One way to dot this is to use a reagent or coreactant that has built into its structure some functionality that allows it to be subsequently extracted into an aqueous phase. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is an example of such a reagent. The pendant dimethylamino functional group makes an excess reagent or coproduce or byproduct basic and so soluble in aqueous acid.

A functional fragment that can be used in this way but has rarely been adopted is the p-dihydroxy-boryl benzyl function.  This substructure appears in the Dobz protecting group for peptide synthesis [D.S. Kemp and David C. Roberts, Tet. Lett. 52, 4629-4632, 1975]. The dihydroxyboryl group forms a strong covalent linkage with the sodium salt of chromotropic acid [1,8-dihydroxynaphthalene-3,6-disulfonic acid] which is very soluble in water.

In the absence of complexing species, boronic acids are in reversible equilibrium with their cyclic trimers and water. Other species containing the group may be partially converted to Boronic anhydrides.

Although many reactions can be conducted in the presence of the free Boronic acid function  as a second option the Boronic acid can itself be protected as the N-methyldiethanolamine complex. N-methylethanolamine is of course itself readily taken into water in a workup. 

The Upper Critical Solution Temperature (UCST) between Acetonitrile and Water

I have always been unsure of the behaviour of mixtures of acetonitrile and water. In some places it is lauded for the usefulness of liquid-liquid partitioning between the two of them while I also see plenty of recrystallizations from homogeneous mixtures of acetonitrile and water. 

Recently in an old US Pat. 4,954,260 filed in 1989 I found the linking piece of data. Water and acetonitrile have an upper critical solution temperature (UCST) of -0.4 C. That is to say below -0.4 C they are generally immiscible  That is to say the two phases each contain both ingredients but they do give two liquid phases. Above this temperature, they constitute a single homogeneous phase. Thus, if you try a recrystallization by heating a mixture of acetonitrile and water you will be working with a homogeneous liquid and even if you cool the solution in ice there will still be one liquid phase.

Pyridine-Water Selective Precipitation with Pyridine Recovery

 

Dissolution of a solute in a water-miscible solvent followed by crystallization or precipitation of the solute by gradual or portion-wise addition of water is an established method of separation and purification.  It is frequently applied to the separation of mixtures of different polymers.

 Solvents commonly used are methanol or ethanol. When lower alcohols are used with small molecule substrates it amounts to the same thing or at least strongly resembles crystallization from mixed alcohol-water solvent. When more expensive organic liquids are used as solvents to be practical at scale there must exist a cheap straightforward method to recover that solvent.

Pyridine is miscible with water in all proportions. It can be used to purify solutes or separate mixtures of solutes by the gradual addition of water so as to cause fractional precipitation. Typically one starts with something like a mixture of 5 parts pyridine and 1 part solute which can be warmed to dissolve what may be a solid or oily mixture; then, one gradually adds water with vigorous stirring until faint turbidity persists. At this point, optionally, a small amount of pyridine (a drop or two at the laboratory scale) can be added to just clear the haziness. Crystallization may begin after some time. In Aleksandra Smoczkiewiczowa and Jan Bielawny's paper in  P. Zakresu Towarozn. Chem.,Wysza Szk. Ekon. Poznaniu, Zesz. Nauk., Ser. 1 1970 No. 36, 149-62, it says that their cholesterol oxidation mixture was dissolved in a 5-fold amount of pyridine and by addition of water fractionally precipitated about 15% androstenolone acetate.

 Pyridine is somewhat expensive as solvents go. No obvious simple means to recover the pyridine when the precipitation is complete makes this an infrequently used methodology  Pure pyridine cannot be recovered by distillation because pyridine/water forms an azeotrope. Fortunately, there is a technical trick that does achieve this separation. Pyridine is not particularly soluble when sodium hydroxide is dissolved into the aqueous pyridine so the addition of enough caustic causes pyridine-water to separate into two phases. The pyridine layer can be separated and the mostly- layer discarded.

Persilylation and its Uses

 

The KiloMentor blog emphasizes the usefulness of simple, robust, scalable methods for work-ups and isolations in organic chemical process development.

Biphasic organic solvent systems such as methanol/hexane can in principle be very useful for the simple extractive separation of components of a reaction mixture. The trick for success is to get partition ratios that are neither too small (<0.2) or too large (>5).

The idea being explored in this blog is whether persilylation of a mixture of solutes from a completed reaction could give a modified mixture that could be separated by liquid-liquid extraction between two immiscible aprotic solvents.

While it is true that most biphasic organic solvent systems comprise at least one protic component and such a solvent would use up all the silylating agent and prevent substrate silylation, there are aprotic solvents that can be mixed and retain two liquid phases. Cyclohexane forms two liquid phases with any one of acetonitrile, propionitrile, nitromethane, nitropropane, dimethylsulfoxide, dimethylformamide or dimethylacetamide. Hexane and heptane would likely behave similar to cyclohexane.  Sulfolane and t-butyl methyl ether are both aprotic and only partially miscible. 

KiloMentor proposes that silylation of all the components of a mixture to be separated should either decrease some and retain unaltered some of their polarities and so perhaps cause their partitioning between the component phases of a two-phase solvent pair to become more competitive. Smaller partition ratios could make a couple of stages of counter-current extraction feasible for separation.

Disclaimer

Please be warned that this methodology has not been experimentally verified in any situation that I know about.  What I can say is it is simple enough to work and I cannot see any particular difficulty.

I have always urged my coworkers to make a clear distinction between facts and theory and this is my effort to do the same.

Making the Silylation Facile

To proceed in this way, a practical method to persilylate all the applicable functional groups in all the components in a reaction mixture is necessary. A further practical consideration is that such silylation procedure must be inexpensive; otherwise, the additional reagent cost will make the procedure uncompetitive with alternative separation means.  Fortunately, it has long been known that there are catalysts for silylation, which allow chemists to use the convenient and inexpensive hexamethyldisilazane reagent for all functional groups.  Although this has been in the literature for many years, it is infrequently used and seems to have today vanished from our chemical toolboxes.

Cornelis A. Bruynes and Theodorus K. Jurriens, then scientists at Gist-Brocades in Delft Netherlands, published a paper called Catalysts for Silylations with 1,1,1,3,3,3-hexamethyldisilazane in J. Org. Chem. 47, 3966-3969 1982.  They reported that the following compound types could be trimethylsilylated using the title reagent and an appropriate one of their catalysts with yields of typically more than 90%:

Alcohols, phenols, carboxylic acids, hydroxamic acids, carboxylic amides, and thioamides, sulfonamides, phosphoric amides, mono and dialkyl phosphates, mercaptans, hydrazines, amines, NH groups in heterocyclic rings, and enolizable β-diketones

The silylation times were in all cases no more than two hours and the catalyst concentration is typically from 0.001-10.0 mole percent.

Silylation Catalyst Structures

Although many catalysts are claimed (there is a corresponding patent  EP81200771.4 now expired), five were used in most examples:

• Saccharin [81-07-2]
• Sodium saccharin [128-44-9]
• Bis(4-nitrophenyl)N-(4-toluenesulfonyl)phosphoramidate [81589-21-`]
• Tetraphenylimidodiphasphate [3848-53-1]
• Bis-(4-nitrophenyl)N-trichloroacetyl)phosphoramidate [38187-67-6]

The registry numbers for these catalysts are given in square brackets.

Methods of Application of this Idea

There are two variants of this idea. In one, all the solutes in a reaction mixture are persilylated and allowed to partition between the two immiscible solvents. In the second, all the solutes in a reaction mixture are mixed with the two immiscible solvents and the silylating reagents are added and the mixture is analyzed as the competitive silylation proceeds and the partitioning of unsilylated, partially silylated, and completely silylated materials accumulate in the two different phases. This second is a kinetic silylation with simultaneous partitioning. 

To use this either strategy all that ought to be necessary would be to

• make a solvent change into acetonitrile, propionitrile, dimethylacetamide, dimethylformamide, nitromethane or nitroethane, whichever is appropriate for the separation trial
• add the minimum necessary amount of a catalyst
• add the calculated amount of hexamethyldisilazane
• heat for the requisite time to get either a complete or another requisite degree of silylation of the mixture with the expulsion of the co-product ammonia
• adjust the solvent volumes so that the biphasic mixture will be produced at the appropriate temperature
• cool to that temperature if necessary
• separate the phases
• repeat extraction if necessary
• hydrolyze the silyl derivatives and recover the products from their respective phases

Potential Problems

It will only be determined by actual experiment with a particular mixture of solutes  how high a relative concentration of the solutes can be worked with before the biphasic solvent mixture goes homogeneous. Obviously, there is some point where the concentration of the solutes will wreck the balance of solvent properties that allows the two phases to coexist.

As is always the case if one adds something to promote a separation that facilitating agent must itself be separated in the end. So it is with the catalyst, which must remain in one or the other phase along with some elements of the mixture being separated.

Another Possible Approach

Consider the possibility of partitioning a reaction mixture between two of these partially immiscible solvents and then with mild stirring adding a silylation catalyst followed by an insufficient amount of a silylating agent such as hexamethyldisilazane.

What would happen?

I would think that whichever solute silylates faster will be partitioned into the less polar hydrocarbon layer where it would be protected from further reaction. The reagent trimethylsilyldiethylamine is probably the most sterically demanding silylating agent one could try to get kinetically controlled silylation.

Using the Zinin Reaction to Prepare Pure Aromatic Regioisomers

In an effort to choose from among the synthetic reaction schemes created by retrosynthetic analysis,  it is often an unconscious assumption that all of the same functional groups in an intermediate react with about the same ease. Thus, it is assumed that all instances of aldehyde, ketone, nitrile, nitro etc. display commensurate reactivity.  The only common exception to this is that sometimes a distinction is drawn between the same functionality attached to an aryl as opposed to an alkyl group. The combined electronic and steric effects in the vicinity of a particular functional group are considered inconsequential to rough first-order planning.  
In the case of a structure with two different functional groups of the same class,  ie two ketones, this simplification most often is a good one because to obtain a quantitatively selective reaction in which only one of two functional group of the same class reacts, the more reactive group must transform more than 100 times faster than the other. This is true because when the reaction is 99% complete, the final 1% of starting material must be more reactive than the 99% of product, which could react further at that second less responsive functional group. Thus, if one reactivity is not one hundredfold greater than the other, the reaction cannot be expected to be quantitative and for practical purposes selective (kinetic control assumed here).

This reasoning explains the widespread use of protecting groups when a substrate contains two functionalities of the same type and the reaction of one only is required. However, there are documented cases where the same functional groups, in two different environments, but in the same molecule, react at usefully different rates.  When the two nominally identical functional groups are in two separate molecules, this can be the basis for separating the mixture by reaction.  When the competing reactivity is between the same groups within the same substrate, the reaction becomes a practical process step that leads to even more complete distinguishing of the functional entities. The reaction is an intramolecular competition.

Suppose one is presented with a mixture of regioisomers: 4-methylethylbenzonitrile and 2-methylethylbenzonitrile.  Although each isomer contains a nominal nitrile, the nitrile groups are not equally reactive. For example, it is reported that ortho substituted aryl nitriles do not readily for imidates by reaction with ethanol and anhydrous hydrogen chloride. We can confidently predict that 2-methylethylbenzonitrile (2-isopropyl benzonitrile) will be unreactive. 

The low reactivity of hindered ortho-substituted aromatic compounds is fairly well known. A less known instance is the application of the sulfide reduction useful for the preparation of isomerically pure aromatic nitro-compounds and anilines.

Thomas R. Nickson wrote a research article[ J. Org. Chem. 1986, 51, 3903-3904] that taught. a specific case. When 3-trifluoromethyl toluene is nitrated the compound formed in the largest amount is the 2-nitro-3-trifluoromethyl-toluene.  It could be separated and purified from the other region-isomers because it was the only isomer than did not undergo the Zenin reduction to an aniline by treatment with sodium sulfide and sulfur. Dr. Nickson however also taught that 3-methyl benzaldehyde and 3-methyl benzoic acid both nitrated preferentially in the 2 position.  From my own experience,  I know that the compound 3,4-dichlorobenzaldehyde nitrates preferentially in the 2-position.  It is possible that all 1,3-substituted compounds with one electron-withdrawing group and one electron-donating group, nitrate preferentially in the 2 position. All of these may be separable by their failure to react in the Zenin reduction!  Nickson tells us that one electron-withdrawing group besides the nitro itself  is advantageous to achieve a fast reduction. Even so, he was able to make 2-nitro m-xylene and separate it cleanly, although in poor yield, by reducing the other isomers, but this reduction went slowly. Also, when the two substituents were both ortho-para directing the yield of the 2 isomer is much lower (10%) as in the case of m-xylene. It is not clear whether the reaction scheme would work with two deactivating groups meta to each other.

Thus, the same general approach could be used to make a variety of polysubstituted compounds with specific substitution patterns. The nitro group has the advantage that it can be reduced to primary amine and then removed completely or converted to a range of other functional groups by diazotization. 1,2,3-substituted aromatics would be available. Similarly, it could be used to prepare a 1,3 disubstituted isomer without adding any substituent.  Suppose one treats toluene with sufficient brominating agent to dibrominated predominantly and then separated out only the dibromides by distillation.  There could be five compounds: the 2,3; 2,4-; 2,5, 2,6-- and 3,4- dibromides. If one mono-nitrates this mixture, only three of these compounds could give a mono nitro compound in which the nitro would have two ortho substituents. If without attempting purification, one uses the Zinin reduction, all the nitro compounds with zero or one ortho substituent would be reduced to amines. Extracting an organic solution of the reaction products with aqueous acid can be expected to remove these substances from the organic phase. Four specific compounds: 3,4-dibromo-2-nitrotoluene; 2,4-dibromo-3-nitro-toluene; 3,6-dibromo-2-nitro-toluene; and 3,5-dibromo-4-nitrotoluene.  Of these only two are likely to be present in significant amounts, because of the directing influences of methyl and bromine on the second bromination.  These two are: 3,4-dibromo-2-nitro-toluene and  2,4-dibromo-3-nitro-toluene. After reduction to the corresponding anilines, there will be a predictable difference in the pKas of the two amines which will allow their separation. 2,4-dibromo-3-amino-toluene will have its amine flanked on each side by the sterically bulky bromines that will also be electron-withdrawing, making it a very weak base. The remaining compound:  3,4-dibromo-2-amino-toluene will be not as weak a base, because it will have the electron-donating methyl in one ortho position.  Consequently protonation will not be as severely inhibited.

The compound 3,4-dibromo-2-amino-toluene, more properly named 2,3-dibromo-6-methylaniline is in a position to be diazotized and reduced to give back 3,4-dibromotoluene.

Using Different Rates of Ester Hydrolysis to Separate Ester Mixtures

Organic synthesis research devotes a substantial amount of time searching for reactions, which proceed selectively so that difficult separations are not needed to obtain pure products. At the same time, it is known that acids and bases, most frequently represented as carboxylic acids or amines, are characteristically easier to separate from each other because of the sensitive effect of substituent patterns on their pKas. It would be very useful if more functional groups could be similarly dependably purified. 
Esters are common derivatives of carboxylic acids and esters can be hydrolyzed to the carboxylic acids easily in high yield in moist solvents. Free acids can conversely be esterified in high yield. Is there a capacity to purify reaction product mixtures, comprising esters by selective hydrolysis? This is not a question typically asked by organic synthesis chemists. The answer, although it was known to us during our undergraduate or graduate studies, has probably since faded away. 
Esters are quite sensitive both to electronic and to steric factors in their relative rates of hydrolysis. Newman’s 'Rule of Six' states that the rate of hydrolysis of an ester is inversely related to the number of atoms which are located four bonds away from the carbonyl carbon or put another way, six atoms away from the attacking nucleophilic atom. From example, in the literature, it can be seen that isomeric compounds differing significantly (i.e. a difference of four substituents six atoms away) can have rates of hydrolysis under the same conditions differing by a factor of 50 or more. 
W shall examine the case in which esters, one in each of two molecules of a product mixture, differ in reactivity by a factor of 50 to consider whether a practical separation would be possible. Additionally and for simplicity we shall assume that the conditions of hydrolysis are selected to give unimolecular reaction kinetics for both the major and minor isomer. It should be noted that in the case where the mechanisms of hydrolysis of the esters are different, the separation is usually even simpler and can often be solved simply by the intuitive application of this information to select differentiating reaction conditions. 
For the development of a general mathematical treatment, 
Let [A]t be the concentration at time t of the major substance
Let [B]t be the concentration at time t of the minor substance
Let [A]to be the concentration at time 0 of the major substance
Let [B]to be the concentration at time 0 of the minor substance 
-d[A]t/dt = k [A]t 
-d[B]t/dt = 50 k [B]t 
This would be true as we have postulated if the rate of hydrolysis of B is 50 times that of A. 
By integrating and subtracting these equations from each other we see how time is related to the ratios of esters at the beginning of hydrolysis and at any time during the hydrolysis 
log {[A]t/[B]t} = (50-1) kt/2.303 + log {[A]to/[B]to} 
rearranging  49kt/2.303 = log {[A]t/[B]t} - log {[A]to/[B]to} 
and solving for t; t = 2.303 {log ([A]t[B]to/[B]t[A]to)}/49 k 
Thus we can calculate the time required to achieve any particular ratio of esters remaining. 
Given that for a unimolecular reaction the rate is related to the half time by 
k=0.693/ t½[A] where t½ is the half life of the major, slower hydrolyzing reaction constituent under the hydrolysis conditions we can substitute and get 
t = 2.303 t½[A] { log ([A]t[B]to /[B]t[A]to)}/( 49(0.693)) 
The half life of a hydrolysis can be approximated without knowing the structure or the concentration of an ester or even separating it from its mixture with the minor ester. The material is simply hydrolyzed until its residual spot is equivalent to a spot of one-half the original concentration when quantitatively equal volumes are spotted. This can be done simply by following the reaction by tlc. The original molar ratio of the mixture can be estimated either by tlc, by integration of appropriate signals in the nmr, or by other means convenient for the particular case. 
We know the ratio of esters present in the mixture before hydrolysis which is [B]to / [A]to. Let’s suppose it is 9/1 or 90% the major isomer, for an example. We can choose the desired enrichment or the ratio of major ester to minor ester at the end of enrichment, that is [A]t / [B]t. Let us set it at 50/1; that is 98% pure. Now the log term becomes simple number and we can solve for time of hydrolysis required to reach that enrichment in units of the half time for the hydrolysis of the major isomer. 
In the case of a 90 to 10 molar composition where the half time for the major A components hydrolysis was 300 minutes, the time for enrichment to 98% purity would be just under 54 minutes. 
We can intuitively see that only a small amount of the desired A component would be destroyed in that time, so it would be a useful separation. 
The degree of enrichment/purification that needs to be reached before the main component of the mixture will purify itself further, (during crystallization for example), is estimated based on experience with similar compounds; then the time for the competitive hydrolysis can be calculated as a fraction of the hydrolysis half time of the major component. After this period, acid-base extraction is applied to separate the mixture of esters and acids and the enriched material recovered. The aqueous fraction of course will be enriched in the minor, more easily hydrolyzed material. 
The same thing is stated in more qualitative terms in the statement that among aliphatic carboxylic acids those of primary structure are esterified readily with an alcohol and a mineral acid catalyst whereas those in which the carboxyl is joined to a quartenary carbon react sluggishly, probably because the alkyl groups dominate so much of the space in the neighborhood of the carboxyl group that they block the formation of a protonated intermediate. The alkyl groups combine to break up the required solvation shell around the charged activation intermediate and raise its free energy slowing the reaction. 
This is even more striking among benzoic acid or heterocyclic acid systems when there are two ortho substitutuents. Meyer in 1894 investigated the response of aromatic acids to attempted esterification under the conditions of refluxing 3-5 hours a solution of aromatic acids in methanol containing 3% hydrogen chloride or by saturating a methanol solution with HCl in the cold and allowing the solution to stand overnight. Doubly ortho substituted materials yielded little or no ester. Even a single ortho substitutent exerted a significant blocking effect compared to benzoic acid. The carboxyl of salicyclic acid which has an ortho hydroxyl must be performed five times as long to give methyl salicylate in reasonable quantity. This difference in reaction rates may be able to be increased further by using a larger alcohol in the esterification. This would add an unfavorable equilibrium to the already slow forward reaction rate. Fieser & Fieser’s Organic Chemistry Third Edition. pg.671-673. 
Although one might think that such thinking is only applicable to simple aromatic substitution problems, when structures become even more complex carboxyl and amines can be hindered by even quite remote parts of a structure in terms of intervening bond distance and steric hindrance can come into play. 
An aldehyde or ketone functional group positioned strategically with respect to the ester function in one of a similar pair of ester compounds can result in a difference in rate of hydrolysis between them of up to five orders of magnitude. U.R. Chatak and J. Chakravarth, Chem.. Comm. 1966, 184 teach such a situation.
A compound that comprises a gamma keto acid has been shown by C. Djerassi and A.E. Lippman, [ JACS 1955, 72, 1825] to be hydrolyzed much faster than a compound without such ketone.  Such a situation is also taught by K. Kemp and Mary L. Mieth, Chem. Comm. 1969, 1260. 2-carboethoxy cyclohexanone is hydrolyzed 69 times faster than ethyl 2-cyclohexylacetate, the same structure without a ketone. Analogously, 2-carboethoxycyclopentanone is hydrolyzed 199 faster than ethyl cyclopentylacetate. Clearly such differences would be sufficient to achieve a simple kinetic hydrolysis selective hydrolysis and separation.
Of course, the best means for differentiating between esters is an enzyme. We are familiar with using enzymes to hydrolyze one enantiomer of a pair of mirror image compounds in a racemate. It follows from this, however, that enzymes should be able to even more easily distinguish esters of distinctly different structures. In the past this was not a productive path because the most likely result would have been that both esters were not substrates for the enzyme. Today many more esterases are available and it is quite likely that an appropriate one can be found to selectively hydrolyze one ester structure in the presence of another. Of course if the compound that hydrolyzes is chiral, the enzyme may only hydrolyze one of the chiral pair. Besides a separation one would achieve a resolution in the same pot!

Nitriles Separated by Reaction and Extraction

Although mixtures of carboxylic acids or mixtures of amines are each fit for separations based on extractions at controlled pHs, most functional groups are not so easy to isolate from each other. Kilomentor thinks a good deal about how to simplify separating molecules with the same functional group in slightly different structural environments.  Although it has not been demonstrated in the literature yet, two different molecules each with a nitrile functionality but differing in the steric environments around them can likely be separated by selective reaction followed by a simple acid-base extraction.

Nitriles are known to react smoothly with azide in a 3+2 cycloaddition to give 1,2,3,4 tetrazoles. This is a ‘click chemistry’ reaction . Cycloadditions are typically quite sensitive to steric environment. Thus, although these reactions are generally fast, it is likely that conditions can easily optimized to get good selectivity between cyanide groups in different molecules using an insufficient amount of azide.  The result will leave a nitrile in one substrate untouched and the nitrile in the other substrate converted essentially completely to tetrazole.  The beauty of this is that these tetrazoles have the acidity of carboxylic acids and can be extracted into water with alkali. Thus the tetrazole derivative removes the reactive nitrile substrate from the organic phase leaving the unreactive nitrile substrate clean for a simple recovery.

Two references that I could locate concerning the kinetics of the reaction of nitriles with azide are: Khimiya Geterotsiklicheskikh Soedinenii (1992) (9) 1214-17, which is in Russian [C.A. 11; 8945a, 8948a]; and Inorganica Chimica Acta (1985). 102(2), 157-62 that does the condensation with the nitrile coordinated in a Co(III)complex.

The synthesis of tetrazoles from nitriles and azide has been studied intensively because of its relevance to the preparation of the sartan family of drugs. Relevant patents are US5744612, US6040454, WO2005014602, WO2007054965 and CN1718574